"COMPOSITION CONTAINING STATINS AND OMEGA-3 FATTY ACIDS"

Abstract

A combination is described comprising at least one omega-3 fatty acid, optionally esterified or salified, at least one statin, Coenzyme Q10, resveratrol, at least one policosanol, pantethine, selenium, and zinc. This combination is endowed with a synergistic effect and is useful in the treatment of disease forms due to insulin resistance and in cardiovascular diseases.

Full Text

Composition containing statins and omega-3 fatty acids
The present invention relates to a combination of active ingredients
and to compositions containing this combination in medical use and in
the preparation of medicaments useful for the treatment of type 2 dia-
betes and cardiovascular diseases.
Diabetes is a widespread disease throughout the world and is associ-
ated with major clinical complications involving the microvascular dis-
trict, such as diabetic retinopathy, diabetic neuropathy and nephropa-
thy, and the macrovascular district, such as atherosclerosis, peripheral
vasculopathies, myocardial infarct and stroke.
Insulin resistance, which characterises type 2 diabetes and its micro-
and macrovascular complications is also involved in syndrome X, poly-
cystic ovary syndrome, obesity, hypertension, hyperlipidaemias and
hypercholesterolaemias (J. Am. Osteopath. Assoc, 2000 Oct.;
100(10):621-34; Jama, 2002 Nov., 27;288(20):2579-88).
It is known that hyperlipidaemias, hypercholesterolaemias and hyper-
tension play a decisive role in the onset of coronary heart disease
(CHD).
It is also known that an increase in glycosylation of proteins is in-
volved in the above-mentioned complications of diabetes (Diabetologia
2001 Feb; 44(2):129-46).
Said complications constitute a serious threat to the life and well-being
of the individual.
Various clinical forms of diabetic disease are known, the most common
being type 2 and type 1 diabetes. Type 2 diabetes is characterised by
reduced sensitivity to the action of insulin (insulin resistance) and
gives rise to an increase in insulin levels in the body in an attempt to
compensate for this deficiency and to a consequent increase in glucose

levels. Numerous reports have confirmed the involvement of insulin
resistance in many disease conditions in addition to type 2 diabetes
itself, such as dyslipidaemia, obesity, arterial hypertension and certain
macrovascular and microvascular manifestations characteristic of dia-
betic disease itself. The combination of insulin resistance and obesity,
hypertension and dyslipidaemia is known as Syndrome X.
Drugs used for many years such as the biguanides and sulphonylurea
drugs are available on the market for the treatment of type 2 diabetes.
Many of these, such as, for example, methformin, present gastrointes-
tinal disorders, danger of acidosis in conditions of renal, cardiac, he-
patic, pulmonary insufficiency, etc., as side effects. The sulphonylureas
have episodes of hypoglycaemia as their possible side effects. Drugs
recently introduced onto the market are the thiazolidinediones, whose
side effects such as liver toxicity, increased LDL cholesterol, weight
gain and oedema have given cause for concern.
Hyperlipidaemia is a serious aspect of diabetic disease, constituting,
together with the hypertension which is often present, a risk factor for
atherosclerosis and for cardiovascular disease which is the primary
cause of death in diabetes.
Cardiovascular disease is recognised as the primary cause of death in
the industrialised countries with a high standard of living.
The social cost is enormous, both in terms of disability and invalidity
of subjects suffering from it, and in terms of the actual cost of health
facilities and insurance.
Dyslipidaemia is often associated, also as a consequence, with diabe-
tes.
In WO 02/43659 a combination of statin, docosahexanoic acid, vitamins
E, C B6 and B12, folic acid and calcium is described to reduce the risk
factors for cardiovascular disease, such as hypercholesterolaemia and

hypertension. In this document there is never any mention of insulin
resistance.
Ever increasing attention is being devoted to the so-called risk factors
recognised as underlying these diseases, and there is still a perceived
need for a medicament capable of acting on the various sources of this
pathological picture, without, at the same time, being associated with
severe side effects, which, as in the case of certain antidiabetic drugs,
may even make it necessary to discontinue the therapy.
Summary of the invention
It has now surprisingly been found that a certain combination of sub-
stances, known for their specific pharmacological actions, is particu-
larly indicated for the treatment of insulin resistance, and of the
pathological aspects related to it, as well as of cardiovascular diseases.
The combination according to the invention comprises essentially at
least one omega-3 fatty acid, optionally esterified or salified, at least
one statin, Coenzyme Q10, resveratrol, at least one policosanol,
pantethine, selenium and zinc.
The unique combination according to the present invention exerts a
surprising effect on insulin resistance, which is not predictable on the
basis of our knowledge of the individual components thereof, and, in
any event, their combination leads to an unexpected synergistic effect.
The advantage of having such a combination is therefore evident to
experts in the field. It is possible, in fact, to treat insulin resistance,
and the pathological forms related to it, particularly as regards the
implications of abnormal lipid status, and, at the same time, the com-
plications or risks affecting the cardiocirculatory system.

The combination according to the present invention can also be used
for the treatment of cardiovascular diseases, without there necessarily-
being any need to treat insulin resistance.
Therefore, one object of the present invention is a combination com-
prising at least one omega-3 fatty acid, optionally esterified or salified,
at least one statin, Coenzyme Q10, resveratrol, at least one polico-
sanol, pantethine, selenium, and zinc.
The combination according to the invention can also comprise other
useful elements, without this substantially impairing the activity.
Another object of the present invention is a pharmaceutical composi-
tion containing the above-mentioned combination, optionally in a mix-
ture with one or more pharmaceutically acceptable vehicles or excipi-
ents.
The combination according to the present invention can also be formu-
lated as a food supplement, which constitutes a further object of the
invention.
Other objects of the present invention are various uses of the above-
mentioned combination as a medicament, in particular for the prepa-
ration of a medicament for the treatment of insulin resistance and type
2 diabetes, with antilipaemic action and a protective action on the car-
diovascular system.
In particular, the present invention provides for the use of the above-
mentioned combination for the preparation of a medicament useful for
the treatment of diseases involving insulin resistance, such as type 2
diabetes, Syndrome X, polycystic ovary syndrome, obesity, hyperten-
sion, hperlipidaemias and hypercholesterolaemias.
The medicament according to the invention can be used to treat the
individual disease states or to exert a preventive or protective action

against them, or to treat a complex pathological picture that includes
one or more of the therapeutic aspects seen above. For example, a me-
dicament with a combined action for the treatment of type 2 diabetes
and insulin resistance and an antilipaemic and protective action on the
cardiovascular system, particularly in certain severe forms of type 2
diabetes associated with obesity.
Detailed description of the invention
The combination according to the present invention consists essen-
tially of active ingredients which are known in the medical field and
already used in clinical practice. Therefore, they are very easy to pro-
cure, inasmuch as they are products which have been on the market
for some time and are of a grade suitable for human or animal admini-
stration.
The statins are a known class of drugs used for lowering cholesterol
levels. Statins are available on the market or can be prepared accord-
ing to known methods described in the literature.
Any statin is suitable for the purposes of the present invention. Exam-
ples of statins are simvastatin, lovastatin, fluvastatin, pravastatin,
atorvastatin, cerivastatin and rosuvastatin. Among these, the one pre-
ferred is simvastatin.
According to the present invention, it is also possible to combine a
number of statins, depending on their pharmacological characteristics
and on the basis of the common knowledge of experts in the field.
The omega-3 fatty acids are known for their triglyceride-lowering ef-
fects and for their effects in raising the levels of high-density lipopro-
teins (HDL). These fatty acids can be obtained by synthesis or, pref-
erably, from fish oil. Inthat case, it is possible to use various mixtures
of omega-3 fatty acids depending on their characteristics. Preferably,
the omega-3 fatty acids are the long-chain ones (from 20 to 22 carbon

atoms). The ones most preferred are 5,8,11,14,17-eicosapentanoic acid
(EPA) and cis 0,13,16,19-docosahexanoic acid (DHA). In a preferred
embodiment of the invention, the omega-5 fatty acid is cis
4,7,10,13,16,19-docosahexanoic acid (DHA), most preferably in a ratio
of 1:1. These omega-3 fatty acids can optionally be esterified or salified
to pharmaceutically acceptable derivatives, with alcohols or bases, re-
spectively. The omega-3 fatty acids, or their esters or salts, alone or in
mixtures thereof, can be procured on the market, or can be prepared by
known methods. The mixtures can be specifically formulated for the
combination according to the invention.
Coenzyme Q10 is now so well known in its human use that it requires
no particular explanation and the substance is available on the mar-
ket. Experts in the field can refer to the patent documents filed by the
present applicant, where this substance is amply described.
Similar considerations also apply to resveratrol.
The policosanols are long-chain aliphatic alcohols. Examples of polico-
sanols are triacontanol, hexacosanol, hexacontanol, ecocontanol, tetra-
cosanol, dotriacontanol, and tetracontanol. The policosonal can be pre-
sent as such or in the form of an extract from natural products that
contain it, e.g. wheat or rice germs, the waxy cuticle of sugar cane, or
Ginkgo biloba leaves. See, for example, WO 99/06039.
Pantethine is used on compositions for hair cosmetics and also in com-
positions for the treatment of dyslipidaemias, as described, for exam-
ple, in WO 2004/041257. It is therefore a well-known compound avail-
able to the expert in the field.
Selenium and zinc are commonly used in food supplements, as de-
scribed in several patents, e.g. EP 0 797 993 and US 6.602.512.

As already mentioned, the individual components have long been used
in human subjects, and therefore their pharmaco-toxicological profiles
are known.
This implies that, apart from the consideration of the synergistic effect
demonstrated here below, the dosages and ratios of the individual
components can be determined by the expert in the field with normal
preclinical and clinical trials, or with the usual considerations regard-
ing the formulation of a dietetic product.
The amounts of the individual compounds advised for the preparation
of a pharmaceutical composition for human use are the following.
Omega-3 fatty acid: from 500 mg to 2 g/day, preferably 1 g/day;
Simvastatin; from 10 mg to 40 mg/day, preferably 10 mg/day;
Coenzyme Q10: from 5 mg to 50 mg/day, preferably 10 mg/day;
Resveratrol: from 1 mg to 5 mg/day, preferably 2.5 mg/day;
Policosanols: hexacosanol: from 5 mg to 15 mg/day, preferably 10
mg/day;
Pantethine: from 10 mg to 30 mg/day, preferably 20 mg/day;
Selenium: from 25 ug to 75 ug/day, preferably 50 ug/day;
Zinc: from 5 mg to 15 mg/day, preferablylO mg/day.
The pharmaceutical composition can have a unitary form, in which the
active ingredients are present in a single pharmaceutical form (tablet,
sachet, capsule, vial) or the active ingredients can be administered in a
coordinated sequential manner. In the latter case, the pharmaceutical
composition can be formulated, supplying the components in separate

containers, accompanied by instructions for their sequential admini-
stration.
The compositions covered by the present invention are entirely conven-
tional and are obtained with methods that are common practice in the
pharmaceutical industry. According to the administration route opted
for, the compositions will be in solid or liquid form, suitable for oral,
parenteral or intravenous administration. The compositions according
to the present invention contain, along with the active ingredient, at
least one pharmaceutically acceptable vehicle or excipient. Particularly
useful may be formulation adjuvants such as, for example, solubilising
agents, dispersing agents, suspension agents and emulsifying agents.
A general reference work is Remington's Pharmaceutical Sciences
Handbook, latest edition.
The following examples further illustrate the invention.
Example 1
Antidiabetic and serum lipid-lowering activity in db/db mice
Mutations in laboratory animals have made it possible to develop
models that present non-insulin-dependent diabetes associated with
obesity, hyperlipidaemia and insulin resistance and that enable us to
test the efficacy of new antidiabetic compounds (Reed and Scribner,
Diabetes, obesity and metabolism 1: 75 - 86, 1999).
A much used genetically diabetic mouse model is the C57BL/KsJ db/db
mouse.
The genetic basis of this model is a defect in the leptin receptor gene
which gives rise to leptin resistance and leads to hyperphagia, obesity,
hyperinsulinaemia and insulin resistance, with subsequent symptoms
of insufficient insulin secretion and hyperglycaemia (Kodama et al.,
Diabetologia 37: 739 - 744, 1994; Chen et al, Cell 84: 491 - 495, 1996).

Since hyperglycaemia is accompanied by obesity and insulin resis-
tance, the db/db mouse has characteristics that are close to those of
type 2 diabetes in man and is useful for assaying insulin-sensitising
compounds.
The C57BL/KsJ db/db mice used in the experiments were supplied by
Jackson Lab (via Ch. River). After 10 days of acclimatisation in stan-
dard conditions (22 ± 2°C; 55 ± 15% humidity; 15-20 air changes/hour;
12 hour light-darkness cycle with light from 7 a.m. to 7 p.m.) on a
standard 4 RF21 diet (Mucedola), blood samples were taken in post-
absorption conditions (fasting from 8.30 a.m. to 4.30 p.m.) from the
caudal vein with the aid of a Jelco 22G catheter (Johnson and John-
son). Glucose, insulin, triglyceride, cholesterol, free fatty acid and urea
levels were checked in the plasma to ensure well-matched distribution
of the mice in the treatment groups.
At the start of treatment, the body weight of the animals was checked
and monitoring of the animals' consumption of water and feed was
scheduled.
The mice were divided into groups and treated orally twice daily with:
Omega-3 fatty acid (EPA +DHA 1:1) 200 mg/kg;
Simvastatin 100 mg/kg;
Omega-3 fatty acid (200 mg/kg) + simvastatin (100 mg/kg);
Omega-3 fatty acid (200 mg/kg) + simvastatin (100 mg/kg); Coenzyme
Q10 (50 mg/kg) + resveratrol (5 mg/kg) + policosanols (hexacosanol 25
mg/kg) + pantethine (100 mg/kg + selenium (0.5 µg/kg) + zinc (2.5
mg/kg).

In the course of the experiment, serum glucose levels, glucose toler-
ance (OGTT), a number of lipid status variables and weight gain were
monitored.
The combination according to the invention was capable of lowering
serum glucose levels in the feeding condition (Table 1); in the post-
absorption condition (Table 2); and in the fasting condition (Table 3);
and capable of improving glucose tolerance (Table 4), and of reducing
the levels of fructosamine, an indicator of protein glycosylation (Table
5) which, as mentioned above, plays an important role in the develop-
ment of the micro- and macrovascular complications of diabetes.
The combination according to the invention also shows good ability to
reduce serum triglyceride levels (Table 6) and to increase HDL-
cholesterol levels (Table 7).
An increase in HDL-cholesterol values constitutes an indicator of a
reduced risk of atherosclerosis and of cardiovascular complications
such as atherosclerosis and infarct.

The results reported above clearly demonstrate the unexpected syner-
gism of the combination according to the present invention, contrary to
what was expected on the basis of the individual components, or even
of the combination of simvastatin and omega-3 fatty acids.

WE CLAIM:
1. Pharmaceutical composition comprising:
a. omega-3 fatty acid: from 500 mg to 2 g/day;
b. simvastatin: from 10 mg to 40 mg/day;
c. Coenzyme Q10: from 5 mg to 50 mg/day;
d. resveratrol: from 1 mg to 5 mg/day;
e. policosanols: hexacosanol: from 5 mg to 15 mg/day;
f. pantethine: from 10 mg to 30 mg/day;
g. selenium: from 25 µg to 75 µg/day;
h. zinc: from 5 mg to 15 mg/day;
optionally in a mixture with at least one pharmaceutically acceptable vehicle or excipient, such
as herein described.
2. Composition as claimed in claim 1, wherein the omega-3 fatty acid is selected from cis
5,8,11,14,17-eicosapentanoic acid (EPA) and cis 4,7,10,13,16,19-docosahexanoic acid (DHA), one of
their esters or pharmaceutically acceptable salts, wherein EPA and DHA are in a ratio of 1:1.
3. Composition as claimed in claim 1 or claim 2, suitable for the administration in unitary form, or
in coordinated, sequential form.
4. Composition as claimed in any one of claims 1 to 3, in the form of a food supplement for
human or animal.
5. Composition as claimed in any one of claims 1 to 3, which is capable of being used as a
medicament.
6. Composition as claimed in any one of claims 1 to 3, which is capable of being used for the
preparation of a medicament for the treatment of type 2 diabetes and insulin resistance.

7. Composition as claimed in claim 6, which is capable of being used for the preparation of a
medicament with antilipaemic action.
8. Composition as claimed in claim 6, which is capable of being used for the preparation of a
medicament with protective action on the cardiovascular system.
9. Composition as claimed in claim 6, which is capable of being used for the preparation of a
medicament useful for the treatment of diseases involving insulin resistance.
10. Composition as claimed in claim 9, wherein the said disease is selected from type 2 diabetes
and its complications, syndrome X, polycystic ovary syndrome, obesity, hypertension,
hyperlipidaemias and hypercholesterolaemias.
11. Composition as claimed in claim 6, which is capable of being used for the preparation of
medicament with a combined action for the treatment of type 2 diabetes and insulin resistance, and
antilipaemic and protective on the cardiovascular system.

(54) Title: COMPOSITION CONTAINING STATINS AND OMEGA-3 FATTY ACIDS
(57) Abstract: A combination is described comprising at least one omega-3 fatty acid, optionally esterified or salified, at least one
statin, Coenzyme Q10, resveratrol, at least one policosanol, pantethine, selenium, and zinc. This combination is endowed with a
synergistic effect and is useful in the treatment of disease forms due to insulin resistance and in cardiovascular diseases.